The enzyme aldose reductase catalyzes the reduction of glucose to sorbitol and has been implicated in processes leading to certain complications of diabetes, including cataracts, retinopathy, nephropathy, and peripheral neuropathy. For this reason, inhibitors of the aldose reductase enzyme are of considerable medical interest. For current reviews, see: Dvornik, D., Aldose Reductase Inhibition, McGraw-Hill, New York, N.Y., 1987; and, Polyol pathway and its role in diabetic complications, N. Sakamoto, et al., eds., Elsevier Science Publishers, New York, N.Y., 1988.
One of the strongest known aldose reductase inhibitors (ARI) is sorbinil, [4(S)-2,3-dihydro-6-fluorospiro-(4H-1-benzopyran-4,4'-imidazolidine)-2',5' -dione]. Sorbinil and its analogs, defined herein as spirohydantoin derivatives wherein essentially planar benzene and hydantoin rings are connected via a nonplanar pyran ring, are the subject of the following United States patents, all of which are herein incorporated by reference: U.S. Pat. Nos. 4,127,665; 4,130,714; 4,147,795; 4,147,797; 4,181,728; 4,181,729; 4,235,911; 4,286,098; 4,248,882; 4,348,526; and 4,431,828.
Other aldose reductase inhibitors whose molecular structures do not conform to the above-stated definition of sorbinil analogs are also known: tolrestat, N-[[6-methoxy-5-(trifluoromethyl)thio-1-napthalenyl]thioxomethyl]-N-methyl glycine; flavonoids having the basic structure of 3-hydroxyflavone; acetylsalicylic acid (aspirin); diphenylhydantoin (Dilantin.TM.); phenobarbital; sulindac; indomethacin; ICI 105552; alrestatin (AY-22,284); and WF-3681, 3-(2,5-dihydro-4-hydroxy-5-oxo-3-phenyl-2-furyl)propionic acid.
The mechanism whereby sorbinil, sorbinil analogs, and other aldose reductase inhibitors inhibit the activity of the aldose reductase enzyme is unknown, as are the precise structural features that are important to that inhibition. It is known generally that the effect of a drug such as sorbinil depends upon the interaction of the drug molecule with its receptor site, which in this case is considered to be on the aldose reductase molecule. The most important factor in that interaction is the drug molecule's conformation, meaning the three-dimensional spatial arrangement of its atoms and groups, which positions interactive atoms in their most active three-dimensional geometry with respect to the complementary conformation of the receptor site. Interactive atoms are defined as those that may participate directly in chemical mechanisms that include charge-transfer, hydrogen bonding, electrophilic and/or nucleophilic substitutions, and hydrophobic interactions. Interacting atoms include but are not limited to oxygen, sulfur, and nitrogen. The active conformation of aldose reductase inhibitors has been hypothesized from theoretical modeling of molecular orbital calculations. For aldose reductase inhibitory activity the hypothesis identifies two important structural features: an aromatic ring or ring complex (for hydrophobic interaction with the receptor site) and an associated carbonyl group. The carbonyl may be C.dbd.O, as in sorbinil, or C.dbd.S as in tolrestat. Kador, P. F., et al., in Enzymology of Carbonyl Metabolism: Aldehyde Dehydrogenase and Aldo/Keto Reductase, Weiner, H., et al., eds., pp. 243-259, A. R. Liss, New York, 1982; Kador, P. F., et al., Molecular Pharmacology 24: 521-531, 1983.
Precise molecular conformations, as determined by X-ray crystallography studies, have been published for only six aldose reductase inhibitors: 3-hydroxyflavone, aspirin (acetylsalicylic acid), phenobarbital, diphenylhydantoin (Dilantin), sorbinil (Kissinger, C. R., et al., Acta Cryst. C41: 988-990, 1985), tolrestat (Varughese, K. I., et al., Can. J. Chem. 61: 2137-2140, 1983), and WF-3681 (Kissinger, C. R., Acta Cryst. C44: 512-514, 1988).
Some of the aldose reductase inhibitors were known to also act as anti-inflammatory (AI) agents: flavonoids having the structural backbone as in 3-hydroxyflavone, acetylsalicylic acid, sulindac, and indomethacin. Two aldose reductase inhibitors were known to also act as anti-convulsant (AC) agents: diphenylhydantoin and phenobarbital.
The foregoing status of the published art is summarized in TABLE 1, which was tabulated for the purpose of illustrating the present invention. In the Table, six aldose reductase inhibitors for which the molecular conformation had been determined are listed in the left column. The center column lists the IC.sub.50 which is the approximate molar concentration of compound necessary for 50% inhibition of aldose reductase. The Table shows that the IC.sub.50 values range from 10.sup.-8 to 10.sup.-3 M. The right column lists other pharmacological activities, either anti-inflammatory or anti-convulsant activity, that were known for some of these compounds.
TABLE 1 ______________________________________ Additional Aldose Reductase Approximate Pharmacological Inhibitors IC.sub.50 (Molar) Activity ______________________________________ Sorbinil 10.sup.-8 (unknown) Aspirin 10.sup.-4 Anti-inflammatory Hydroxyflavone 10.sup.-6 Anti-inflammatory Diphenylhydantoin 10.sup.-4 Anti-convulsant Phenobarbital 10.sup.-3 Anti-convulsant Tolrestat 10.sup.-8 (unknown) ______________________________________